20-(aliphatic hydrocarbonoxy)-and 20-(substituted aliphatic hydrocarbonoxy)-pregnene-11-oxygenated-3-ones



United States Patent by This invention relates to the synthesis of steroids, and has for its object the provision of a new class of physiologically active steroids, which may be represented by the formula wherein R is selected from the group consisting of hydroxyalkoxy, acyloxyalkoxy and carboxylalkoxy; R is hydrogen, R is BOH and R and R together are 0x0 (0 The preferred acyl radicals of this invention are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, pr-opionic, butyric and tert-pentanoi-c acids), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryl lower alkanoic acids (e.g., phenylacetic and ,B-phenylpropionic acids), the cycloalkane carboxylic and the cycloalkene carboxylic acids.

The compounds of the invention are useful as intermediates or antibacterial agents. They can be administered in a range of 0.1 mg. to 100 mg. per kg. of patient weight. But generally it is preferred to administer the compounds of this invention in a manner known to the art. Thus, the novel compounds of this invention may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.

The final products of this invention are prepared by the process of this invention which entails a number of steps beginning with 12a-methyl-11-ketoprogesterone-3, 20-bisethylene ketal (Compound A) as a starting material.

The following formulae illustrate the process of the invention:

3,351,636 Patented Nov. 7, 1967 CH CH CHOR OAcyI CH3 (EH3 CH8 HOIUOH wherein R is alkylene.

The bisketal (Compound A) of the invention is reduced as by treatment with lithium aluminum hydride to form the 20-hydroxy derivative of the invention wherein R is ethylene (Compound B). This product may be acylated by reacting it with an acid anhydride in the presence of an organic base such as pyridine to form Compound C which in turn may be reacted with an oxidizing agent such as Smiths reagent, i.e., chromic acid sulfuric acid reagent to yield the 3,11-diketo intermediate of the instant invention (Compound D). Compound D may then be deacylated as by treatment with an inorganic basic solution, e.g., potassium hydroxide or sodium hydroxide, to form an end product of the invention (Compound E). Oxidation of Compounds B or E with chromic acid yields a new compound of the instant invention, Compound F.

The following examples illustrate the instant invention. All temperatures are in degrees centigrade unless otherwise stated:

Example 1.-12a-methyl-20-(2'-hydr0xyeth0xy)- pregn-4-ene-3-0ne-115-01 The crude product from the lithium aluminum hydride reduction of 12oz methyl-l1-ketopr0gesterone-3,ZO-bis ethylene ketal and subsequent acid hydrolysis as described in US. Patent No. 3,151,135 is chromatographed on acid alumina. Elution with 10:1 and 5:1 benzenezchloroform yields 12a methyl 11-[3 hydroxy 200a (2 hydroxy ethoxy)-pregn-4-ene-3-one as the main product, while elution with 3:1, 2:1 and 1:1 benzenezchloroform yields 12a methyl a hydroxy 205 (2 hydroxy ethoxy)- pregn-4-ene-3-one. Further elution with chloroform yields the product. Crystallization from aqueous ethanol gives fine needles with a melting point of 202204 C., [a] +119 (CI-I01 c. 1.07), al-c, max. 243 m (e=15,300), A nujol, max. 2.9, 6.0-2, 6.20, 9.0, 9.6 NMR (CDCl methyl singlets at 9.08, 8.94 and 8.571 methyl doublet at 8.931, 'vinyl singlet at 4.331, methylene at 6.26.81, triplet proton at 6.01 and multiplet at 6.651.

Analysis.Calcd for C H O (390): C, 73.80; H, 9.81. Found: C, 73.73; H, 9.64.

Example 2.-12a-methyl-20- (2-acetoxyeth0xy pregn-4-ene-3-one-1 1,8--1

A solution of 1 g. of 12a methyl 20$ (2-hydroxyethoxy)-pregn-4-ene-3-one-1119-01 in 10 ml. of pyridine and ml. of acetic anhydride is stirred at room temperature for eighteen hours. After addition of ice, the precipitate is filtered and washed thoroughly with water. Recrystallization from acetone-hexane yields needles with the following properties: M.P. 162163 C., [a] +114 (CHCI c. 1.00), x alc, max. 243 m (e=l6,000); x nujol, max. 2.9, 5.75, 6.05, 6.20, 8.1, 9.0 and 945 NMR (CDCI methyl singlets at 8.96, 8.57 and 7.941, methyl doublets at 9.10 and 8.941, vinyl proton at 4.341, methylene at 60-68 and 5.81.

Analysis.Calcd for C H O (432): C, 72.19; H, 9.32. Found: C, 71.99; H, 9.26.

Example 3.-12a-methyl-20g- (2'-acet0xyethoxy pregn-4-6ne-3J1-dione To a solution of 9 g. of 12a. methyl-20-(2'-acetoxyethoxy)-pregn-4-ene-3-one-l118-01 in 200 ml. of acetone cooled with an ice water bath is added 18 m1. of chromic acid-sulfuric acid reagent. After the solution is stirred for one hour, isopropyl alcohol is added to destroy the excess oxidizing solution. Upon addition of water a precipitate forms. After filtration and thorough rinsing, the precipitate is recrystallized from acetone-hexane yielding fine crystals with the following characteristics: M.P. 122-124 C., [a] +139 (CHCl;;, 0. 1.05), 7\ alc, max. 236 m (e=15,800); A nujol, max 5.75, 5.90, 6.05, 6.2, 8.02, 8.12, 9.45 and 11.5,u, NMR (CDC1 methyl singlets at 9.26, 8.58 and 7.871, methyl doublets at 8.94, and 8.921, vinyl proton at 4.34, methylenes at 5.88 and 6.591, multiplets at 7.31 and 6.721.

Analysis.Calcd for C H O (430): C, 72.52; H, 8.90. Found: C, 72.46; H, 8.91.

Example 4.12a-methyl-20- (2'-hydr0xyeth0xy pregn-4-ene-3,11-dione A solution of 547 mg. of 12a methyl-20-(2'-acetoxyethoxy)-pregn-4-ene-3,1l-dione in 25 ml. of methanol and 5 ml. of 5% methanolic potassium hydroxide solution is stirred for eighteen hours at room temperature. After neutralization with dilute hydrochloric acid solution the methanol is removed under reduced pressure. Water is then added and the aqueous solution extracted with chloroform. The combined chloroform extracts are washed with salt solution, dried on sodium sulfate and concentrated. Recrystallization of the crude residue from acetone-hexane yields needles with the following properties: M.P. 198199 C., k nujol 2.85, 5.9, 6.02, 6.20, 8.9, 9.4, 10.55 and 11.55,u.

Example 5.12a-methyl-20- (canboxymethoxy pregn-4-ene-3,11-dione A solution of 1 g. of 12a methyl 20$ (2'-hydroxyethoxy)-pregn-4-ene-3-one-1lfi-ol in 25 ml. of acetone cooled with an ice water bath is oxidized with 2 ml. of 8 N chromic acid solution. After the solution is stirred for one hour, isopropyl alcohol is added to destroy the excess acid. Water is added and the resultant precipitate is filtered and washed thoroughly with water. Recrystallization from acetone-hexane yields crystalline product with the following properties: M.P. 203-205 C., [M +138 (CHCl c. 0.99), alc, max. 236 m (e=17,400), A nujol, max. 3.5, 5.82, 5.90, 6.15, 8.22, 8.85, 10.05 and 1l.45 NMR (CDCl,) methyl singlets at 8.59 and 9.221, methyl doublets at 8.90 and 8.871, vinyl proton at 4.291, methylene at 5.971 and multiplets at 7.18 and 6.611.

Analysis.Calcd for C H O (402): C, 71.61; H, 8.51. Found: C, 71.84; H, 8.49.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound of the formula wherein R is selected from the group consisting of hydroxyalkoxy, acyloxyalkoxy and carboxylalkoxy; R is hydrogen, R is fi-OH and R and R together are 0x0 (0 2. A compound in accordance with claim 1 having the name 12cc methyl 20$ (2-hydroxyethoxy) pregn 4- ene-3-one-1 1 8-01.

3. A compound in accordance with claim 1 having the name 12a methyl 205 (2 acetoxyethoxy) pregn 4- ene-3-one-11;3-ol.

4. A compound in accordance with claim 1 having the name 12cc methyl 20.5 (2 acetoxyethoxy) pregn- 4-ene-3,l1-dione.

5. A compound in accordance with claim 1 having the name 12a methyl 20g (2 hydroxyethoxy) pregn- 4-ene-3,l l-dione.

6. A compound in accordance with claim 1 having the name 12a methyl 20E (carboxymethoxy) pregn-4- ene-3,11-dione.

ELBERT L. ROBERTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,351,636 November 7, 1967 Mariano A. Guiducci et a1.

s in the above numbered pat- It is hereby certified that error appear ent requiring correction and that the said Letters Patent should read as corrected below.

Column 1 line 27 for "are" read is column 4, lines 21 to 31, for that portlon of the formula reading ZH read 1H line 3 for "are" read 15 Signed and Sealed this 26th day of November 1968;

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Offic r 

1. A COMPOUND OF THE FORMULA 